Biomedical subjects

N Inamura

Publications and source records attributed to N Inamura.

At least 19 recordsLinked to original sources

PubMed2005

Clinical course of fetal congenital atrioventricular block in the Japanese population: a multicentre experience.

OBJECTIVES: To elucidate the prenatal and postnatal course of fetal congenital atrioventricular block (CAVB) during the past decade in the Japanese population. DESIGN: Retrospective multicentre study. All fetuses with CAVB in 10 Japanese institutions in the period from January 1990 to August 2001 were included. PATIENTS: Of the 48 fetuses with CAVB, 17 had a congenital heart defect (CHD) (14 with left atrial isomerism) and 31 had a structurally normal heart (22 with positive maternal autoantibodies). Gestational age at diagnosis was 15 to 38 (median 26) weeks. RESULTS: Of the 17 fetuses with a CHD, three were aborted, one died before birth, and eight died after birth (three in the neonatal period and five after the neonatal period). Of the 31 fetuses without a CHD, two died before birth and two died after birth. CHD (p = 0.005) and the presence of fetal hydrops (p = 0.05) were significant risk factors for death. However, fetal ventricular and atrial heart rates, gestational age at delivery, and birth weight were not related to death. Transplacental medication of sympathomimetics increased the fetal heart rate in five of eight fetuses treated. Dexamethasone did not improve the degree of heart block in any of the six fetuses treated. Postnatally, pacemakers were implanted in 30 of 40 babies. Four fetuses with maternal autoantibodies had decreased cardiac function. CONCLUSIONS: CHD and fetal hydrops are risk factors for prenatal and postnatal death. The fetal ventricular rate of 55 beats/min did not appear to be a threshold value by which to predict fetal hydrops. Patients with CAVB should be subjected to close long term follow up to check for the need for pacemaker implantation or for late onset cardiac dysfunction.

Anti-Arrhythmia Agents↗

PubMed2001

Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive disorders associated with a defect in the nucleotide excision repair (NER) pathway required for the removal of DNA damage induced by UV light and distorting chemical adducts. Although progressive neurological dysfunction is one of the hallmarks of CS and of some groups of XP patients, the causative mechanisms are largely unknown. Here we show that mice lacking both the XPA (XP-group A) and CSB (CS-group B) genes in contrast to the single mutants display severe growth retardation, ataxia, and motor dysfunction during early postnatal development. Their cerebella are hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. Reduced neurogenesis and increased apoptotic cell death occur in the cerebellar external granular layer. These findings suggest that XPA and CSB have additive roles in the mouse nervous system and support a crucial role for these genes in normal brain development.

Animals↗

PubMed2001

Involvement of c-Jun N-terminal kinase and caspase 3-like protease in DNA damage-induced, p53-mediated apoptosis of cultured mouse cerebellar granule neurons.

In the previous studies, we have demonstrated that the tumor suppressor gene p53 is required for DNA strand break-induced neuronal apoptosis in organotypic slice cultures of cerebellum as well as in dissociated cerebellar neuron cultures. In this study, we further investigated the role of p53 in neuronal apoptosis, by examining whether caspases and c-Jun N-terminal kinase (JNK) are involved in the DNA strand break-induced apoptosis. The protein level of phospho-JNK increased in p53 wild-type mouse cerebellar granule neurons after exposure to bleomycin. On the other hand, the response was not observed in cerebellar granule neurons of p53-deficient mice. Caspase-3-like protease was activated and poly(ADP-ribose) polymerase (PARP) was cleaved in the bleomycin-induced apoptosis. Caspase-3-like protease inhibitor decreased the number of TUNEL-positive but not p53- or c-Jun-positive neurons in bleomycin-induced death. These results suggest that JNK and caspase-3-like protease are involved in the signaling cascade of DNA strand break-induced, p53-dependent apoptosis.

Animals↗

PubMed2000

Role of p53 in DNA strand break-induced apoptosis in organotypic slice culture from the mouse cerebellum.

Apoptosis occurs not only in mitotic cells but also in postmitotic neuronal cells. We previously suggested that the tumor suppressor gene p53 is required for DNA strand break-induced apoptosis in dissociated culture of cerebellar granule neurons. In this study, we examined the role of p53 in apoptosis using organotypic slice culture of cerebellum from p53 null and wild-type mice. Exposure to bleomycin significantly increased the numbers of TUNEL-, p53-, and c-Jun-positive neurons in the wild-type mouse cerebellar internal granular layer (IGL) and Purkinje cell layer (PL). However, in p53-deficient mice, these responses were not observed. These results are consistent with our previous observations in dissociated neuronal culture showing that the amount of c-Jun protein increases significantly after addition of bleomycin in p53 wild-type cerebellar granule cells. The results presented here also indicate that p53 is involved in DNA strand break-induced apoptosis of fully postmitotic central nervous system neurons and suggest that c-Jun expression occurs downstream of p53 expression.

Animals↗

PubMed2000

Potentiation of the vascular response to kinins by inhibition of myocardial kininases.

Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B(2) receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9 nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L). Desensitization of B(2) receptors was induced by the administration of BK (0.2 micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B(2) receptors is overcome by increasing BK concentrations, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction but point to a very high activity of BK degradation in the vicinity of the B(2) receptor in combination with a stimulation-dependent reduction in receptor affinity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

A nonpeptide mimic of bradykinin blunts the development of hypertension in young spontaneously hypertensive rats.

We tested whether FR190997, a nonpeptide B(2) agonist, prevented the development of hypertension in young spontaneously hypertensive rats (SHR), which secrete less kallikrein into the urine than do Wistar-Kyoto rats. An intra-arterial (IA) injection of FR190997 (0.3 to 30 nmol/kg) caused dose-dependent hypotension in conscious Sprague-Dawley rats. Although the maximum hypotensive potency of FR190997 equaled that of bradykinin, its action lasted approximately 10 times as long. Hoe140 (100 nmol/kg IA) significantly blocked the hypotensive response induced by FR190997 (10 nmol/kg). Atropine (100 nmol/kg IA) did not affect this response. A selective infusion of FR190997 into the renal artery induced natriuresis and diuresis in anesthetized rabbits. A continuous infusion (2 nmol. 10 mL(-1). h(-1) per rat) of FR190997 into the abdominal aorta of young SHR (6 weeks old, n=6) for 6 days significantly (P<0.05) reduced mean blood pressure to 114+/-6 (day 2) and 110+/-6 (day 5) mm Hg, from 149+/-7 and 162+/-6 mm Hg, respectively, in vehicle-infused rats (n=6). At 8 days after continuous infusion (day 14), mean blood pressure (148+/-5 mm Hg) in FR190997-infused rats remained significantly (P<0. 05) lower than that in vehicle-infused rats (190+/-6 mm Hg), almost the peak value. The mesenteric artery isolated from FR190997-treated rats (day 14) had lower contractile sensitivity to norepinephrine than that from vehicle-treated rats. These results suggested that the continuous infusion of a nonpeptide B(2) agonist may prevent hypertension if performed in the critical phase.

Age Factors↗

PubMed2000

Involvement of the renal kallikrein-kinin system in furosemide-induced natriuresis in rats.

This study examined whether the renal kallikrein-kinin system (KKS) is involved with furosemide-induced natriuresis in rats. Intravenous administration of furosemide (10 mg/kg) to anesthetized rats infused with physiological saline (saline) increased renal KK excretion as well as urine volume and urinary excretions of sodium, chloride and potassium. The change in the increase of renal KK excretion by furosemide at a dose of 1.0 mg/kg relative to the control was larger than that of urine volume. Pretreatment with a B2-receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657, 100 mg/kg), significantly inhibited the furosemide-induced natriuresis by 58.6%. The effect of FR173657 on the furosemide-induced natriuresis was also examined in hypotonic saline-loading rats. Similar to the saline-loading rats, urinary excretion of sodium collected during the first 8 h in metabolic cages significantly reduced by 22.4% when FR173657 (100 mg/kg) was given concurrently with furosemide (100 mg/kg) and hypotonic saline (5% of body wt.). These results indicate that furosemide increased renal KK excretion through a mechanism different from a washout mechanism and induced natriuresis partly through an augmentation of the renal KKS following the increase in renal KK excretion in both the saline- and hypotonic saline-loading rats.

Animals↗

PubMed2000

The effects of temperature on the mechanical performance in fatigued single muscle fibers of the frog induced by twitch and tetanus.

Muscle fatigue induced by consecutive twitches or tetani was studied in single skeletal muscle fibers of the frog, Rana japonica. The fatigue by twitch appeared sooner after the start of stimulation at lower temperatures (2-5 degrees C) than at higher ones (15-20 degrees C), while the fatigue by tetanus appeared sooner at higher temperatures. When a twitch-fatigued fiber was bathed in a solution with caffeine (15 mM), the contracture force was much higher than the fatigued force, while in tetanus fatigue, the force by caffeine was not different from the fatigued force. The length-force relation in fatigued fibers was compared with that in pre-fatigue at low and high temperatures. It was noticed that the ascending limb of the length-force curve in fatigued fibers by twitch was lower than that in pre-fatigue at the low temperatures; namely, the fatigue by twitch was more marked in shorter muscle length, while no marked change in the length-force relation was detected in the tetanus fatigue at the low and high temperatures. The maximum shortening velocity, measured by the slack test, decreased in both types of fatigue. These results suggest that the fatigue by twitch may be mainly due to the failure of activation of the contractile system, while in the fatigue by tetanus, the rate of the interaction between actin and myosin may be impaired due to the change in intracellular chemical environment.

Adenosine Triphosphate↗

PubMed1999

Characterization of FR 172357, a new non-peptide bradykinin B(2) receptor antagonist, in human, pig and rabbit preparations.

FR 172357, a new non-peptide antagonist of the kinin B(2) receptor was tested in three isolated vessels, the human umbilical vein, the rabbit jugular vein, and the pig coronary artery, to evaluate its antagonistic activities against bradykinin. FR 172357 displaced to the right the concentration-response curves of bradykinin. The displacements were parallel to the controls without reduction of the maximum effect in the human umbilical vein and in the rabbit jugular vein, but not in the pig coronary artery. Schild plots confirmed that FR 172357 acts as a competitive antagonist in the human umbilical vein (pA(2) 8.65) and in the rabbit jugular vein (pA(2) 9. 07), and as a non-competitive antagonist in the pig coronary artery (pK(B) 10.14). FR 172357 is selective for the kinin B(2) receptor since it does not influence the effects of Lys-des-Arg(9)-bradykinin in the human umbilical vein, in the rabbit aorta, and in the pig renal vein. It is specific because it does not affect the contractions induced by angiotensin II, noradrenaline, 5-hydroxytryptamine, or endothelin-1 in the human umbilical vein. It, however, interacts with the tachykinin NK(1) receptor of the rabbit jugular vein and pig coronary artery. Compared to other bradykinin B(2) receptor antagonists, FR 172357 emerges as a very potent compound, which may represent a choice for experimental (and clinical?) applications.

Animals↗

PubMed1999

K+ loading, but not Na+ loading, and blockade of ATP-sensitive K+ channels augment renal kallikrein secretion.

This study aimed to examine whether K+ loading or Na+ loading augments renal kallikrein (KK) secretion. It also investigated the effect of blockade of renal ATP-sensitive K+ channels on renal KK secretion. Rats were administered 50 mmol/kg body weight of KCl. Twelve-hour collected urine was measured for urinary excretion of K+ and Na+ and urinary activity of renal KK. Increases in urinary excretion of K+ and Na+ by K+ loading accompanied an increase in renal KK secretion. In another experiment, rats were infused intravenously with a solution of 75 mM K+ and 75 mM Na+, 150 mM Na+ or 300 mM Na+ for 150 min under anesthesia. Urinary KK activity was measured in urine collected every 30 min. Renal KK secretion began to increase within the 30 min infusion of K+ solution and persisted at more elevated levels during the infusion with K+ solution than with Na+ solutions. Furthermore, rats were given intravenous injection of ATP-sensitive K+ channel blocker, either PNU-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl) at a concentration of 10 mg/kg or glibenclamide at 30 mg/kg. Renal KK secretion increased 30 min after administration of both PNU-37883A and glibenclamide. In conclusion, it may be that augmentation of renal KK secretion by K+ loading occurred through an increase in urinary K+ excretion followed by the inhibition of K+ transport from ATP-sensitive K+ channels.

ATP-Binding Cassette Transporters↗

PubMed1999

Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043.

Neutrophil elastase degrades extracellular matrix components and is involved in tissue destruction in several inflammatory states. We examined the inhibition of the elastase activity derived from activated neutrophils in vitro and in vivo by FR134043, disodium-(Z,1S,15S,18S,24S,27R,29S,34S,37R)-29-b enzyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31, 37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,2 8,31,33-octaazatetracyclo[16.13.6.1(24,28).0(3,8)]octatriconta+ ++-3,5,7-trien-5,6-diyl disulfate, an elastase inhibitor with broad specificity, and elucidated the role of neutrophil elastase in pathogenesis of acute inflammation. In a culture of human neutrophils, phorbol myristate acetate (PMA) and calcium ionophore increased elastase activity in the supernatants, which was amplified by co-existing mononuclear leukocytes. Formyl-Met-Leu-Phe stimulated elastase release in the presence of, not without, mononuclear leukocytes. Intratracheal injection of lipopolysaccharide elevated the elastase activity in bronchoalveolar lavage fluid of rats. These elastase activities were significantly inhibited by FR134043. Intratracheal treatment with FR134043 in rats also inhibited the enzyme induced by lipopolysaccharide, though the maximum inhibition was 52%. Ear edema elicited by topical application of PMA in mice was significantly suppressed by pretreatment with FR134043 (38% inhibition at 1 mg/ear). In carrageenan-induced joint injury in rats, plasma extravasation into the synovial cavity was partially and significantly inhibited by FR134043 at 1 mg/knee, while an elastase-specific inhibitor showed no effect. These results suggest that neutrophil elastase is partially involved in tissue damage in acute inflammation provoked by irritants, but not in carrageenan-induced hyperpermeability.

Acute Disease↗

PubMed1999

Pharmacological characterisation of the first non-peptide bradykinin B2 receptor agonist FR 190997: an in vitro study on human, rabbit and pig vascular B2 receptors.

FR 190997, a new kinin B2 receptor agonist of non-peptide nature, has been studied in three isolated vessels: the human umbilical vein (hUV), the rabbit jugular vein (rbJV), and the pig coronary artery (pCA). Bradykinin (BK) contracts the hUV and rbJV through smooth muscle B2 receptors, while it relaxes the pCA through endothelial receptors of the B2 type. Contractions of the hUV and rbJV in response to FR 190997 show slow onset and are not reproducible compared to the rapid and reproducible effect of BK. They reach only 70% and 30% of the BK-induced maximal contractions in the hUV and rbJV, respectively. The effects of FR 190997 are antagonised by HOE 140 and this antagonist shows similar pK(B) values against BK and FR 190997, indicating that the non-peptide agent interacts with the kinin B2 receptor. FR 190997 is inactive as relaxant of the pCA; in this tissue, it acts as a pure and competitive antagonist, with a pK(B) value of 7.6, while HOE 140 acts as an insurmountable antagonist (pK(B) 9.3). When tested as an antagonist, FR 190997 inhibits also the contractile effects of BK in the hUV (pK(B) 7.8) and in the rbJV (pK(B) 7.6). FR 190997 is selective for the B2 receptor since it does not interact with the B1, and is specific since it does not affect the contraction evoked by 5-hydroxytryptamine, endothelin-1, and noradrenaline in the hUV, or the relaxation induced by substance P in the pCA. FR 190997 shows therefore different pharmacological profiles in various preparations, acting as a partial agonist in the hUV and especially in the rbJV and as a pure antagonist in the pCA. This new compound could be of interest in understanding how non-peptide agonists may activate receptors for peptides.

Adrenergic beta-Antagonists↗

PubMed1999

Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and antagonist (FR 173657).

Pharmacologic parameters for a novel non-peptide bradykinin (BK)-B2 receptor agonist, 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoylcinnamidoacetyl]-N-+ ++methylano] benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR 190997) (pEC50, ED50 values) and for the antagonist (E)-3-(6-acetamido-3-pyridyl)-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl ) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide (FR 173657) (pIC50, ID50 values) were measured using conventional contractile B2 receptor bioassays from rabbit, guinea pig and rat tissues and by mean of animal blood pressure models performed on anesthetized animals in the same species. In vitro assays (on the rabbit jugular vein and the guinea pig ileum) demonstrated that both the onset and duration of action of FR 190997 are prolonged compared to BK. These in vitro effects of FR 190997 strongly desensitized upon repeated tissue applications. Similar pEC50 values (7.7) were measured on the rabbit and the guinea pig tissues. In vivo, when injected intraarterially, FR 190997 produced hypotensive responses in rabbits and guinea pigs with ED50 values of 3.7 +/- 0.5 and 8.9 +/- 3.6 nmol/kg, respectively. Both the contractile and the hypotensive effects of FR 190997 were abolished by pretreating tissues (1 microM) or animals (0.1-0.5 micromol/kg) with D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (HOE 140) or FR 173657. FR 173657 (pIC550 approximately 8.40), as well as other known antagonists (e.g., HOE 140, D-Arg-[Hyp3,D-Phe7,Leu8]BK), inhibited the in vitro myotropic effects of BK on the rabbit, guinea pig and rat tissues. FR 173657 also abrogated the in vivo hypotensive responses elicited by BK in the rabbit (ID50 57 +/- 9 nmol/kg), the guinea pig (ID50 215 +/- 56 nmol/kg) and the rat (ID50 187 +/- 50 nmol/kg). The in vivo duration of action of FR 173657 was significantly lower in the rabbit (= 20 min) than in the guinea pig and the rat (> 90 min). It is concluded that the non-peptides FR 190997 and FR 173657 enable efficient activation and antagonism of rabbit and guinea pig B2 receptors. These non-peptide molecules represent a marked progress in medicinal chemistry and may be useful to define the role played by the kallikrein/kinin system in vivo.

Animals↗

PubMed1999

Discovery of orally active nonpeptide bradykinin B2 receptor antagonists.

Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been discovered by using directed random screening and chemical modification. These compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes, rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B2 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle contraction at 10(-6) M, and caused parallel rightward shifts of the concentration-response curves to BK on contraction with higher p A2 values. They also blocked human B2 receptor-mediated phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral administrations of these antagonists potently inhibited BK-induced bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, selective, and orally active BK B2 receptor antagonists and that they may have therapeutic potential against inflammatory diseases and pain.

Administration, Oral↗

PubMed1999

Nonpeptide mimic of bradykinin with long-acting properties.

Kinins, members of a family of peptides released from kininogens by the action of kallikreins, have been implicated in a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells and activation of sensory neurons. However, investigation of the physiological actions of kinins have been greatly hampered because its effects are curtailed by rapid proteolytic degradation. We examined the pharmacological characteristics of the first nonpeptide bradykinin receptor agonist 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinolin e (FR190997). FR190997, whose structure is quite different from the natural peptide ligand, but is similar to the nonpeptide antagonists FR165649, FR167344 and FR173657, potently and selectively interacts with the human B2 receptor and markedly stimulates inositol phosphate formation in transfected Chinese hamster ovary (CHO) cells. FR190997 induces concentration-dependent contraction of isolated guinea pig ileum. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration, presumably as a consequence of its resistance to proteolytic degradation. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity at the bradykinin B2 receptor. This compound represents a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.

Animals↗

PubMed1999

Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats.

1 This study aimed to examine whether administration of potassium or ATP-sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium-induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups. 3 Administration of the KATP channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on the potassium-induced increase in renal KK secretion. 6 Renal KK secretion increased in slices of kidney cortex incubated with PNU-37883A within 10 min of superfusion. 7 In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker.

Adamantane↗

PubMed1999

[Vein of Galen aneurysmal malformation: multi-staged feeder clipping in two neonatal cases with intractable heart failure].

The authors reported the surgical experience of two cases of vein of Galen aneurysmal malformation in the newborn, whose congestive high-output cardiac failure was intractable. Along with the intensive care to clinical manifestations of the heart failure, multi-staged feeder clipping was carried out to decrease the high-flow shunt of the malformation. As stages going on, heart failure was relieved gradually and cathecolamines were weaned. Although certain retardation became apparent in both cases, they are showing satisfactory development in the long-term follow up. By the recent advancement of the embolization technique, the embolization appears to have already taken place the treatment of choice for this malformation. According to the neonatal evaluation score of Lasjaunias, the embolization would no longer be recommendation in neonates, whose general condition scored less than eight points. The authors believe, based on our two cases, that multi-staged feeder clipping is one of the effective modality of treatment in neonates of the vein of Galen aneurysmal malformation with severe multiorgan failure.

Cardiac Output, High↗

PubMed1998

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation.

In recent articles we reported the identification of a series of 8-[[2, 6-dichloro-3-[N-methyl-N-[(E)-(substituted)acryloylglycyl]amino]++ +benzy l]oxy]-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists. Optimization of the terminal glycine part and the imidazo[1,2-a]pyridine moiety led to the discovery of a clinical candidate (5, FR173657). With the aim of completion of the structure-activity relationship (SAR) study, we next investigated the roles of the substituents on the central phenyl ring. The results suggested that the 2,6-dichloro or 2, 6-dimethyl groups may play important roles in regulating the conformations of the 1- and 3-substituents and also may interact with hydrophobic pockets of the B2 receptors. Furthermore, according to the results of a molecular modeling study reported in part 1 of this series, we designed and synthesized a series of sterically constrained analogues by replacing the N-methylamide group with cis-amide-like rigid moieties. We discovered several bioisosteres and chemically proved that the N-methylamide moiety adopts the cis-amide form in the active conformation. Extensive chemical modification led to the identification of a novel class of highly potent and orally active non-peptide B2 antagonists represented by a pyrrole derivative (52a, FR193517). Compound 52a inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50s of 0.37 and 0.56 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration.

Administration, Oral↗